Commensal resilience mechanisms in the inflamed intestine

发炎肠道的共生弹性机制

• 批准号: 10799252
• 负责人: Wenhan Zhu
• 金额: $ 5.27万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799252
• 关键词: Address; Award; Bacterial Physiology; Bacteroides thetaiotaomicron; Dimensions; Disease; Genetic; Goals; Gram-Negative Bacteria; Health; Homeostasis; Human; Intestines; Iron; Iron Chelating Agents; Iron Chelation; Knowledge; Mediating; Micronutrients; Modeling; Molecular; Nutritional Immunity; Process; Research; Research Project Grants; Shapes; Siderophores; Starvation; Structure; System; Untranslated RNA; Work; enteric pathogen; experimental study; gut bacteria; gut inflammation; gut microbes; gut microbiome; gut microbiota; in vivo; innovation; insight; iron metabolism; microbial; microbiota; pathogen; programs; resilience; uptake

PROJECT SUMMARY The human gut microbiota is increasingly recognized as having essential functions in human health. However, the microbiota is constantly subjected to challenges such as intestinal inflammation, which drives the microbiota into a perturbed state that can exacerbate diseases. Therefore, microbial resilience, which maintains the structural and functional stabilities of the gut microbiome in the face of perturbations, is critical to host health. The overarching goal of our research program is to elucidate the molecular mechanisms that govern commensal resilience in the inflamed intestine. During intestinal inflammation, host processes known as nutritional immunity starve gut microbes from essential micronutrients such as iron. In contrast to the well-studied strategies that pathogens employ to overcome host nutritional immunity, little is known about how gut commensals survive iron starvation in the inflamed gut. The primary goal of our research program for the next five years is to define the resilience mechanisms that maintain commensal iron homeostasis during gut inflammation. Enteric pathogens overcome nutritional immunity by producing iron-chelating molecules termed siderophores. Here, we show that the model gut commensal Bacteroides thetaiotaomicron (B. theta) acquires iron in the inflamed gut by pirating siderophores from an enteric pathogen that causes intestinal iron limitation. Notably, B. theta captures siderophores using a unique system absent in other Gram-negative bacteria. However, such a capture mechanism can be exploited by enteric pathogens to “re-pirate” siderophores from gut commensals to evade nutritional immunity. In addition to increasing iron uptake, we show that B. theta employs small, non-coding RNAs to orchestrate iron conservation and maintain intracellular iron homeostasis in the inflamed intestine. With this MIRA award, we will define commensal resilience mechanisms by addressing two related but independent questions in fundamental bacterial physiology: 1) How does xenosiderophore acquisition mediate B. theta resilience during gut inflammation? 2) How does B. theta manage intracellular iron homeostasis in the inflamed intestine? We will approach these questions using an interdisciplinary pipeline consisting of cutting-edge omics experiments, bacterial & host genetics, and a mechanistic understanding of bacterial physiology in vivo. The completion of these research projects will reveal the mechanisms by which gut commensals adapt to iron limitation in the inflamed gut and how such adaptation shapes the structural and functional stability of the gut microbiome. The proposed work is innovative because it adds commensal iron metabolism as a previously unappreciated dimension to the intricate interactions between pathogen and nutritional immunity. This work is impactful because it will provide much-needed insights into how interphylum iron metabolism contributes to gut microbiota resilience in the inflamed gut.

项目摘要 人类肠道菌群越来越被公认为在人类健康中具有重要功能。然而， 微生物群经常受到诸如肠道炎症之类的挑战，它驱动了微生物群 进入可能加剧疾病的扰动状态。因此，维持的微生物弹性 面对摄动的肠道微生物组的结构和功能稳定性对于宿主健康至关重要。 我们的研究计划的总体目标是阐明控制共同的分子机制 发炎的肠道中的弹性。在肠道炎症期间，宿主过程称为营养免疫 来自基本微量营养素（例如铁）的饥饿肠道微生物。与研究的策略形成鲜明对比 病原体员工要克服宿主营养免疫，对肠道的生存方式知之甚少 发炎的肠道饥饿。未来五年我们研究计划的主要目标是定义 在肠道注射过程中保持共同铁稳态的弹性机制。肠 病原体通过产生称为铁载体的铁授予分子来克服营养免疫。在这里，我们 表明模型肠道共生菌菌thetaiotaomicron（B。theta）通过 从肠道病原体中盗版铁载体，该病原体导致肠铁的限制。值得注意的是，B。Theta捕获 在其他革兰氏阴性细菌中使用独特系统的铁载体。但是，这样的捕获 肠道病原体可以探索机制，以从肠道分子逃避“重新海盗” sidedephores 营养免疫。除了增加铁的吸收外，我们还表明，B。Theta员工小型，非编码RNA 在发炎的肠道中策划铁保护并维持细胞内铁的稳态。与此 MIRA奖，我们将通过解决两个相关但独立的问题来定义共生的弹性机制 基本细菌生理学中的问题：1）异种载体采集如何介导B. theta 肠道注射期间的弹性？ 2）B。theta如何管理发炎的细胞内铁稳态 肠？我们将使用跨学科的管道来解决这些问题 实验，细菌和宿主遗传学以及对细菌生理学的机械理解。这 完成这些研究项目的完成将揭示肠道的适应铁的机制 发炎的肠道限制以及这种适应如何塑造肠道的结构和功能稳定性 微生物组。拟议的工作具有创新性，因为它添加了共同铁代谢 病原体和营养免疫之间的复杂相互作用的不欣赏维度。这项工作是 有影响力，因为它将提供急需的见解，以了解源代谢如何有助于肠道 发炎的肠道中的菌群弹性。

项目成果

Byproducts of inflammatory radical metabolism provide transient nutrient niches for microbes in the inflamed gut.

炎症自由基代谢的副产物为发炎肠道中的微生物提供短暂的营养生态位。

• DOI: 10.1101/2023.12.08.570695
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Spiga,Luisella;Winter,MariaG;Muramatsu,MatthewK;Rojas,VivianK;Chanin,RachaelB;Zhu,Wenhan;Hughes,ElizabethR;Taylor,SavannahJ;Faber,Franziska;Porwollik,Steffen;Carvalho,TatianeF;Qin,Tian;Santos,RenatoL;Andrews-Polymenis,He
• 通讯作者: Andrews-Polymenis,He